A variety of man-made, inorganic particles cause lung diseases such as pulmonary fibrosis and asthma that are characterized by mesenchymal cell (fibroblast and smooth muscle cell) hyperplasia. The platelet-derived growth factor (PDGF) system appears to be pivotal to the progression of these diseases. Fibrogenic particles (asbestos) and ambient, urban (PM10) particles associated with airway inflammation and asthma induce macrophages to produce several cytokines including interleukin-1b (IL- 1b), basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGF-b1). We have shown that IL-1b and bFGF upregulate the PDGF alpha receptor and increase the mitogenic and chemotactic response of fibroblasts and airway smooth muscle cells to PDGF-AA, -AB and -BB. Furthermore, we discovered that bacterial wall components (endotoxin) induce PDGF receptor upregulation and this may be significant since many ambient particles are associated with surface adhered endotoxins. Thus, inhaled particles that cause fibroproliferative lung disease activate macrophage populations in the lung to signal mesenchymal cells to become more responsive to mitogenic signals (i.e. PDGF isoforms) produced by macrophages, fibroblasts and smooth muscle cells. We also reported that the mitogenic and chemotactic potential of PDGF isoforms is regulated by a2-macroglobulin (a2M), a proteinase inhibitor secreted by lung fibroblasts and macrophages. a2M selectively controls the PDGF-B chain dimers and serves to clear and inactivate PDGF through the a2M-receptor. We postulate that inorganic particles interfere with regulatory mechanisms that normally control the biological activity of PDGF during tissue repair and maintenance. When these regulatory mechanisms are in place, inflammation following injury can be resolved and tissue is repaired. However, dysfunction of these regulatory mechanisms could lead to a fibroproliferative response.